17alpha-fluoro-, 17beta-chlorofluoroacetoxy-and 17beta-methyl-5, 10-methylene and 5,10-seco-5, 19-cyclo-10beta-fluoro androstane derivatives



United States Patent 17oz FLUORO-, 17fi CHLOROFLUOROACETOXY- ANDI7B-METHYL-SJO-METHYLENE AND 5,10- SECO 5,19 CYCLO-lOft-FLUOROANDROSTANE DERIVATIVES Lawrence H. Knox, Mexico City, Mexico, assignorto Syntex Corporation, Panama, Panama, a corporation of Panama NoDrawing. Filed Mar. 19, 1964, Ser. No. 353,256 21 Claims. (Cl. 260-3973)Z a mi In the above formulas, R represents hydrogen, a lower alkyl,alkenyl or alkinyl radical such as methyl, ethyl, propyl, vinyl,propenyl, ethinyl, propinyl, etc., and Z represents a single or a doublebond between C-1 and C-2.

These compounds are anabolic-androgenic agents with, 'a favorableanabolic-androgenic ratio In addition, they have anti-estrogenic,anti-gonadotrophic and antifibrillatory properties, lower the bloodcholesterol level and inhibit the activity of the pituitary gland.

ice

The method for producing the novel compounds of the present invention isillustrated by the following equation:

wherein A represents:

and R has the same meaning as heretofore indicated.

In practicing the process illustrated above, a17fl-hydroxy-S,IO-methylene-19-nor-androstane derivative or a 17 5hydroxy -.5,10 seco 5,19 eyclo 10B fluoro compound (I) is treated wit-h1 to 1.5 molar equivalents of a fiuorinated amine such asZ-chloro-l,1,2-trifiuorotriethylamine, in a suitable organic solvent, ata temperature comprised between room temperature and the steam bath fora period of time of between 5 minutes to 3 hours. The solvent is thenevaporated under reduced pressure, to produce a mixture of thel7-a-fiuoro-(II), 17/8 chlorofluoroacetoxy (III) and 17,8 methyl A (W)corresponding derivatives, which are separated by chromatography onneutral alumina or Florisil.

The solvents suitable for this reaction are acetonit-rile, ethers suchas diethyl ether, isopnopyl ether, dioxane, tetrahydrofuran, Dowanol andthe like, aromatic hydrocarbons such as benzene, -toluene, Xylene, etc.In general, the reaction can be carried out in any organic solventwithout acidic hydrogen.

An additional double bond may be introduced at C-1, C-2 in the5,l0-methylene-19-nor-andnostanes and 5,10-seco-5,19-cyclo-10fl-fluoro-M-androstenes 'by conventional methods, suchas for example, by reflux with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Examples of suitable starting materials for the process of the presentinvention are:

These starting materials are obtained as follows:

5,10 methylene 19 nor A androsten 17,8 ol- 3,- one and5,10-seco-5,19-cyclo-IOfl-fiuoro-M-androstenl7B-ol-3-one are obtained asdescribed in my copending patent application Serial No. 286,931 filedJune 11, 1963, now US. Patent No. 3,184,484 by reaction of l9-hy- 3droxy-M-androstene-S,17-dione with 2-chlor0-1,1,2-trifiuorotriethylamineto produce'a mixture of 5,10-methylene-l9-noraA -androstene-3,l7-dioneand 5,10-seco-5,19- cyclo-1(lfl-fluoro-A -and-rostene-3,17-dione, whichare separated by chromatography. Reduction of these compounds withlithium aluminum hydride gives rise to 5,10- methylene-19-nor-A-androstene-3B,17B-diol and 5,10- seco 5,19,- cyclo 10B fluoro Aandros-tene 3,8, 17/3-diol respectively, which are then selectivelyoxidized at C-3 by reaction with manganese dioxide in chloroform.

Catalytic hydrogenation of 5,lO-methylene-19-nor-Aandrosten-17p-ol-3-one produces the saturated compound, i.e.,5,10-methylene-19-nor-androstan-17p-ol-3-one, as described in mycopending application Serial No. 286,913 filed June 11, 1963.

The la-alkyl, alkenyl and alkinyl substituted derivatives of5,10-methylene-19-nor-androstan-l7fl-ol-3-one are obtained by reactionof 5,IO-methylene-19-nor-A -androsten- 17fi-ol-3-one with a Grignardreagent, as described in my copending application Serial No. 346,074filed February 20, 1964.

Upon dehydrogenation of these lot-substituted compounds ordehydrogenation of 5,10-seco-5,19-cyclo-10fifiuoro-A -androsten17fi-o1-3-one with 2,3-dichloro-5,6- dicyano-1,4-benzoquinone, there areproduced the corresponding l-dehydro derivatives.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

PREPARATION 1 A mixture of 5 g. of1a-me-thyl-5,10-methylene-19-norandrostan-17fl-ol-3-one, 100 cc. ofdioxane and 3.5 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone wasrefluxed for hours. It was then cooled, the 2,3-dichloro-5,6-dicyano-1,4-benzohydroquinone formed during the reaction filtered oil,and the filtrate evaporated to dryness. The residue was dissolved inacetone and filtered through 100 g. of alumina. Crystallization fromacetone-hexane gave 1-methyl-5,10-methylene 19-nor-A-androsten-17flo1-3-one.

In a similar manner, starting from Methyl- 5,10-methylene-19-nor-androstan-17B-ol-3-one, 1a-propyl-5,l0 methylene-19nor-androstan-17B-ol-3-one, 1a-vinyl-5,10-methylene-19-nor-androstan-17fi-ol-3-one, 1a-ethiny1-5,10- methylene-19nor-androstan-l7fl-ol-3-one and 5,10-seco- 5,19-cyclo-10,8 fiuoro-A-androsten-17fi-ol-3-one, there were obtained the correspondingdehydro-derivatives, namely, 1-ethyl-5,1O methyIene-19-nor-A-androsten-17B- ol-3-one, l-propyl-5,l0-methylene 19-nor-A -androsten-17/8-ol-3-one, l-vinyl-S,1O-methylene-19-nor-A -androsten-17fl-ol-3-one, l-ethinyl-SJO-methylene 19-nor-A -androsten-17 3-ol-3-oneand 5,10-seco-5,19 cyclo-lOfl-fluoro- A -androstadien-17p-ol-3-one.

Example I Example 11 To a solution of 2.8 g. of5,10-methylene-19-nor-androstan-17fi-ol-3-one in 20 cc. of anhydrousacetonitrile there was added 1.9 g. of2-chlor0-1,1,2-trifiuorothiethylamine,

the mixture was heated on the steam bath for 15 minutes, evaporated todryness under vacuo and chromatographed onto Florisil, to afford thepure 17a-fluoro-5,10-methylene-19 nor-androstan-B-one,17fi-chlorofluoroacetoxy- 5,10-methylene-l9-nor-androstan-3-one and17,3-methyl- 5,10-methylene-18,19-bisnor-androstan-3-one identical tothose obtained in the preceding example.

Example 111 Example I was repeated but using methylene chloride assolvent, with similar results.

Example IV Example V Example II was repeated but using ether as solvent,with similar results.

Example VI By following the method of ExampleI, the compounds listedbelow under I were converted into the products set forth under II, whichwere separated by chromatography.

Example VII A mixture of 500 mg. of 5,10-sec0-5,19-cyclo-105,170:-difluoro-A -androsten-3-one, 10 cc. of dioxane and 350 mg. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 10 hours. Itwas then cooled, the 2,3-dichloro- 5,6-dicyano-1,4-benzohydroquinoneformed during the reaction filtered olf, and the filtrate evaporated todryness. The residue was dissolved in acetone and filtered through 10 g.of alumina. Crystallization from acetone-hexane gave5,1O-seco-S,19-cyc1o-l0fl,17a-difiu0ro-A l-androsta-i dien-3-one.

In a similar manner, 5,10-seco-5,l9cyclo-10,8-fiuorO- 17,8chlorofluoroacetoXy-A -androsten-3-one and 5,10-seco-S,19-cyclo-10B-fluoro-17fi methyl A4713 18 norandrostadien-3-onewere converted into the corresponding l-dehydro derivatives, namely,5,l-seco-5,l9-cyclo- 10,3 fluoro 17 ,8 chlorofluoroacetoxy-A-androstadien- 3-one and 5,l0-seco-5,l9-cyclo l0fi-fluoro-l7fi methyl- A=l8-nor-androstatrien-3-one,

Example VIII Example I was repeated. but instead of 30 minutes, thereaction mixture was allowed to stand at room temperature for 3 hours,with the same results.

By the same method, 5,10-seco-5,19-cyclo-l0fi-fluoro- A-androstadien-l7fi-ol-3-one was converted into 5,10- seco-5,19-cyclo-108,17oc-difluoro-A -ar1drostadien 3-one,5,10-seco-5,l9-cyclo-lOfi-fluoro-l75 chlorofiuoroacetoxy- A-androstadien-3 one and 5,10 seco-5,19-cyclo-1OB- fluoro-17/3-methyl-A-18-nor-androstatrien-3-one identical to the products inthe precedingexample.

Example IX In accordance with the method described in Example II, thecompounds mentioned below under I were converted into the products setforth under H, which were separated by chromatography on Florisil:

1a-methyl-17a-flu0ro-5,IO-methylene-19-nor-A -androsten-3-one,1a-methyl-l7B-ch10rofiuoro-acetow-5,1O-methylene-lQ-nonA androsten-3oneand 101,17B-dimethyl-5,10-Inethylene-l8,l9- bisnor-A-androstadien-3-one. 1a-ethyl-17a-fluoro-5J0-rnethylene-lQ-nor-AandIoSten-Bcne, 1a-ethyl-l7fl-chlorofluoro-acet0xy-5,10-methylene-IQ-nor-A -androsteu-3-one and methyl-176-methyl-5,10-methylene-18,19- bisnor-A -andr0stadieu-3-0ne.1a-vinyl-17a-fiu0ro-5,IO-methylene-lQ-nor-A -androsten-iione,1u-ethyl-l7B-chlorofiuor0-acetoxy- 5,IO-methylene-l -nor-A-androsten-3-one and 1a-vinyl-17flmethyl-5,IO-methylene-lBJQ- bisnor-A-2 ndrostadien-3-one.1a-ethinyl-17a-fluoro-5,l0-methylene-IQ-nor-N-androsten-3-0ne,la-ethinyl-l7fl-chlorofluoro-acetoxy-5,IO-methylenelQmor-Aandrosten-3-one and la-ethinyl- 17fl-methyl-5,10-methylene-l8,19-bisnor-N -androstadien-li-one.

Lia-methyl-5,10methylene-l9-nor- A -androsten-l7fi-ol-3-one.

la-vinyl-5,10-111ethylene-19mm- A -androstend719-013-0110.

I claim: 1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl and lower alkinyl and Z is selected from the groupconsisting of a double bond and a saturated linkage between C-1 and C-2.

2. l7u-fluoro-5,IO-methylene-l9-nor-androstan-3-one.

3. 17a fluoro 5,IO-methylene-19-nor-A -androsten-3- one.

4. a methyl 17a fluoro-S,l0-methylene-19-norandrostan-3-one.

5. 1a methyl-17a fluoro-S,l0-methylene-l9-nor-A androsten-S-one.

v6. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl and lower alkinyl and Z is selected from the groupconsisting of a double bond and a saturated linkage between 0-1 and 0-2.

7. 171-3 chlorofluoroacetoxy 5,10 methylene-19-norandrostan-3-one.

8. 17 3 chlorofluoroacetoxy 5,10 methylene-19-nor- A -androsten-3-one.

9. A compound of the following formula:

wherein Z is selected from the group consisting of a double bond and asaturated linkage between C-1 and C-2.

14. 5,10 seco 5,19 cyclo-10B,17a-difluoro-A -androsten-3-one.

15. 5,10 seco 5,19 cyclo l0fl,l7a-difluoro-A -androstadien-3-one.

16. A compound of the following formula:

l5 reg wherein Z is selected from the group consisting of a double bondand a saturated linkage between C-l and C-2.

17. 5,10 seco 5,19-cyclo-l0fi-fluoro-l7p-chlorofiuoroacetoxy-A-androsten-3-one.

7 8 v 18. 5,10 -,seco 5,19-cyclo-1OB-fiuoro-17 8-ch1orofiuoro- 20. 5,10seco 5,19-cyc1o-1O/B-fiuoro-17fi-methy1-A acetoxy-A -androstadien-3-one.18-nor-androstadien-3-one.

19. A compound of the following formula: 21. 5,10 seco 5,19 cyclo 10/3fluoro-17fl-methyl- A 1 -18-1'10r-andIOStatI'i6n-3 -0ne. (17H: 5 a rReferences Cited by the Examiner l UNITED STATES PATENTS F 2 3,013,02712/1961 Ruz cka et a1 260--397.4

k 1 I 10 LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: